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Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen Within Lung Tissue

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Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen Within Lung Tissue Published OnlineFirst June 1, 2010; DOI: 10.1158/1940-6207.CAPR-09-0162 Research Article Cancer Prevention See perspective p. 692 Research Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen within Lung Tissue Sibele I. Meireles1, Gustavo H. Esteves3, Roberto Hirata, Jr.4, Suraj Peri2, Karthik Devarajan2, Michael Slifker2, Stacy L. Mosier1, Jing Peng1, Manicka V. Vadhanam6, Harrell E. Hurst6, E. Jordao Neves4, Luiz F. Reis5, C. Gary Gairola7, Ramesh C. Gupta6, and Margie L. Clapper1 Abstract Lung cancer is the leading cause of cancer deaths in the United States, surpassing breast cancer as the primary cause of cancer-related mortality in women. The goal of the present study was to identify early molecular changes in the lung induced by exposure to tobacco smoke and thus identify potential targets for chemoprevention. Female A/J mice were exposed to either tobacco smoke or HEPA-filtered air via a whole-body exposure chamber (6 h/d, 5 d/wk for 3, 8, and 20 weeks). Gene expression profiles of lung tissue from control and smoke-exposed animals were established using a 15K cDNA microarray. Cytochrome P450 1b1, a phase I enzyme involved in both the metabolism of xenobiotics and the 4- hydroxylation of 17β-estradiol (E2), was modulated to the greatest extent following smoke exposure. A panel of 10 genes were found to be differentially expressed in control and smoke-exposed lung tissues at 3, 8, and 20 weeks (P < 0.001). The interaction network of these differentially expressed genes revealed new pathways modulated by short-term smoke exposure, including estrogen metabolism. In addition, E2 was detected within murine lung tissue by gas chromatography-coupled mass spectrometry and immu- nohistochemistry. Identification of the early molecular events that contribute to lung tumor formation is anticipated to lead to the development of promising targeted chemopreventive therapies. In conclusion, the presence of E2 within lung tissue when combined with the modulation of cytochrome P450 1b1 and other estrogen metabolism genes by tobacco smoke provides novel insight into a possible role for estro- gens in lung cancer. Cancer Prev Res; 3(6); 707–17. ©2010 AACR. Introduction a better prognosis after lung cancer diagnosis as com- pared with men (3). It has been suggested that estrogens Lung cancer is the leading cause of cancer death in the may affect the susceptibility of women to lung cancer United States and has surpassed breast cancer as the (2, 5–7). primary cause of cancer-related mortality in women (1). The individual variation in efficiency of cellular pro- Exposure to cigarette smoke is estimated to account for cesses such as detoxification, metabolic activation, adduct approximately 90% of all lung cancers (2). Epidemiol- formation, and DNA repair influences individual suscep- ogic and clinical data suggest a gender difference in the tibility to the tumorigenic effects associated with tobacco biology of lung cancer (3, 4). Women appear to have an smoke exposure. Detoxification enzymes play a critical increased susceptibility to tobacco carcinogens but have role in the metabolism of both tobacco-related carcino- gens and endogenous compounds (including hormones) Authors' Affiliations: 1Cancer Prevention and Control Program and within the human lung (8). Activation of the aryl hy- 2Department of Biostatistics and Bioinformatics, Fox Chase Cancer drocarbon receptor signaling pathway by components of Center, Philadelphia, Pennsylvania; 3Center of Sciences and Technology, University of Paraíba State, Campina Grande, Brazil; 4Department of tobacco smoke such as polycyclic aromatic hydrocarbons Mathematics and Statistics, University of São Paulo; 5Hospital Sírio leads to transcriptional upregulation of a number of genes Libanês, São Paulo, Brazil; 6Department of Pharmacology and Toxicology/ including members of the cytochrome P450 (CYP) fam- Brown Cancer Center, University of Louisville, Louisville, Kentucky; and 7Graduate Center for Toxicology, University of Kentucky, Lexington, ily, in particular, CYP1B1 and CYP1A1. These phase I en- Kentucky zymes activate procarcinogens such as benzo(a)pyrene Note: Current address for S.I. Meireles: Grupo Fleury, Sao Paulo, Brazil (BaP) to reactive electrophilic intermediates, which Corresponding Author: Margie L. Clapper, Fox Chase Cancer Center, are in general detoxified to inactive water-soluble conju- 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-4301; gates for excretion by phase II enzymes (i.e., glutathione Fax: 215-214-1622; E-mail: [email protected]. S-transferase, UDP-glucuronosyl-transferase, sulfotrans- doi: 10.1158/1940-6207.CAPR-09-0162 ferase, and catechol-O-methyltransferase). Upregulation ©2010 American Association for Cancer Research. or downregulation of these enzymes, in turn, can influence www.aacrjournals.org 707 Downloaded from cancerpreventionresearch.aacrjournals.org on September 28, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst June 1, 2010; DOI: 10.1158/1940-6207.CAPR-09-0162 Meireles et al. the fate of reactive intermediates in the body, leading to the tained in ambient air for the same period of time. Our en- accumulation or clearance of metabolites; thus influencing hanced understanding of the early molecular events that cancer incidence. contribute to lung tumor development is anticipated to It is well established that estrogen can stimulate cell sig- aid in the identification of promising chemopreventive tar- naling and proliferation in the breast via estrogen receptor gets that can be examined readily for their efficacy in the A/J (ER)–dependent and ER-independent pathways (9). The model of current and former smoke exposure. role of estrogen as a procarcinogen is also based on the ability of its metabolites (catechol estrogens) to induce Materials and Methods genetic damage. The formation of catechol estrogens is cat- alyzed by CYP1B1, CYP1A1, CYP1A2, and CYP3A4 in Tobacco smoke exposure several tissues. The most carcinogenic catechol estrogen is Female A/J mice, 8 to 9 weeks of age, were purchased 4-hydroxyestradiol (4-E2), an estrogen agonist that binds from The Jackson Laboratory and maintained with free access to the ER with greater affinity and for longer periods of time to food (AIN-93G, Harlan Teklad Global Diets) and water. than the parent compound 17β-estradiol (E2; ref. 10). 4-E2 is Body weights were recorded weekly to monitor growth. produced primarily by CYP1B1 and is quickly oxidized to All procedures were approved by the Institutional Animal highly reactive quinones that bind to DNA, forming depur- Care and Use Committee of the University of Kentucky. inating DNA adducts (11) that induce genetic mutations. Mice were randomized into six treatment groups (six per Although smoking cessation decreases the risk of lung group) and exposed to either tobacco smoke or HEPA-filtered cancer, ex-smokers remain at a significantly increased risk ambient air (control). Exposure of mice to sidestream for cancer for decades. Development of an efficacious smoke was carried out in whole-body chambers for 6 hours chemopreventive regimen for lung cancer has been hin- per day, 5 days per week for 3, 8, and 20 weeks. Sidestream dered by our inability to identify early molecular targets smoke was generated from the University of Kentucky for intervention as well as those individuals who would ben- reference cigarette (2R4F), and the suspended smoke partic- efit most from treatment. The majority of the molecular tar- ulate concentration in the chamber atmosphere was main- gets that have been identified to date represent late events in tained at approximately 40 to 45 mg/m3. tumorigenesis, as indicated by their presence in established Exposure of mice to smoke was ascertained by measur- tumors. These include biomarkers of tumor cell prolifera- ing levels of urinary cotinine, ethoxyresorufin deethylase tion (i.e., EGFR, TP53, KRAS, RB, and BCL2) and angiogen- activity in lung microsomes, and cytochrome P450 1a1 esis stimulation factors (i.e., VEGF, FGF, and MMP), among (Cyp1a1) protein. Significant increases of these markers others (12). Whereas these late events aid in selecting treat- were observed in smoke-exposed groups over controls at ment options and predicting prognosis, early events (in par- all time points. Cotinine was measured routinely in urine ticular, those occurring during the preneoplastic phase) can samples (ELISA Kit, OraSure Technologies) collected from be used as targets for chemopreventive intervention, thus three to five mice per group over 24 hours. Cotinine values blocking tumor formation. Limited attention has been given ranging from 4 to 10 μg cotinine/mg creatinine were ob- to the identification of early biomarkers of lung cancer risk. served in urine from smoke-exposed mice as compared The A/J mouse and its genetically related A/HeJ strain with picogram levels in the unexposed control groups. have been shown to be the strains that are most responsive Lobes of lungs from three to four animals per treatment to cigarette smoke exposure as compared with AKR, BALB/ group were pooled, and lung microsomes were prepared C, C3H/HeJ, C57BL/6, CAST/Ei, DBA, SWR, and 129/Svi by differential centrifugation (9,000 × g and then mice (13). A/J mice develop lung adenomas/adenocarci- 100,000 × g for 60 minutes). The protein content of the nomas spontaneously and, following exposure to tobacco resulting fraction was determined using a commercial kit smoke, readily develop additional lung tumors that from Bio-Rad. The ethoxyresorufin deethylase activity of are similar to human lung adenocarcinomas with respect lung microsomes was determined using a modified fluori- to pathologic features, genetic alterations, and aberrant sig- metric resorufin assay (16). Aliquots of the microsomal naling pathways (14). By allowing the animals to recover in protein were separated on 12% SDS-polyacrylamide gels fresh air for 16 weeks following 20 weeks of smoke expo- and subjected to Western blot analysis. Blots were probed sure, Witschi and colleagues (15) were successful in enhanc- with a polyclonal rabbit anti-rat Cyp1a1 antibody (diluted ing lung tumor development in smoke-exposed mice.
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